Utilizing Abemaciclib in Combination with Endocrine Therapy in High- Risk Early Breast Cancer: The monarchE Trial

Kaitlyn Bartley, PharmD
Ambulatory Oncology Clinical Pharmacist
Georgia Cancer Center/AU Health
Augusta, GA

Breast cancer is the most common malignancy among females in the United States; there were an estimated 279,100 new cases in 2020.¹ Globally, 90-95% of these patients are diagnosed with ear­ly-stage disease, which generally has a favorable prognosis with low risk of recurrence when treated with standard of care therapies.² Of those diagnosed with early-stage disease, 70% have cancers that are hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-).³

Although treatment can vary in each patient based on risk of recurrence, endo­crine therapy (ET) is the standard of care in the adjuvant setting for patients with HR+ and HER2- disease and is associated with a significant reduction in risk of recurrence and death. However, up to 20% of patients may experience disease recurrence within the first 10 years due to ET resistance.⁴

Patients with high-risk clinical and/or pathologic features, such as large tumor size, high histologic grade, lymph node involvement, or high Ki-67 score, are at a greater risk for recurrence.⁴ For this reason, optimizing adjuvant therapy to minimize the risk of early recurrences or metastases is vital to this population of patients.

Abemaciclib is an oral, continuously dosed, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor and has shown promise in attenuating ET resistance.⁵ It is approved for use as both monotherapy and in combination with ET for the treatment of HR+, HER2- metastatic breast cancer. These approvals were based on significant improvements in progression-free survival (PFS) and objective response rate (ORR) seen in the MONARCH-1, MONARCH-2, and MONARCH-3 trials, which supports an evalua­tion of abemaciclib in the adjuvant setting.⁶

The monarchE Trial
MonarchE was an international, open-label, randomized, phase III trial that investigated the addition of abemaciclib to standard adjuvant ET in patients with HR+, HER2-, node-positive, high-risk early breast cancer. High-risk features were defined as patients with 4 or more positive pathologic axillary lymph nodes or 1-3 positive axillary lymph nodes with at least one of the following: tumor size ≥ 5 cm, histologic grade 3, or a centrally assessed Ki-67 ≥ 20%.

Patients were randomly assigned (1:1) to standard of care ET with or without abemaciclib (150 mg twice daily for two years) and continued ET for 5-10 years as clinically indicated. Patients were stratified according to previous chemotherapy, menopausal status, and geographic region. Radiotherapy and chemotherapy (neoadjuvant and adjuvant) were allowed and randomization must have occurred within 16 months of definitive breast cancer surgery. Patients who received prior ET for the prevention of breast cancer, had previous CDK4/6 inhibitor use, and those with inflammatory or metastatic breast cancer were excluded.⁴

The primary end point was invasive disease-free survival (IDFS) and was measured from the date of randomization to the date of first occurrence of ipsilateral invasive breast tumor recurrence, local/regional recurrence, distant recurrence, death attributable to any cause, contralateral invasive breast cancer, or second primary non-breast invasive cancer. Secondary end­points included distant relapse-free survival (DRFS), overall survival (OS), and safety.⁴

Results
A total of 5,637 patients from 603 sites in 38 countries underwent randomization over a two-year period. Baseline character­istics were well balanced between treatment groups. Patients were predominantly female (99.4%) and postmenopausal (56.5%) with a median age of 51. Almost 60% of patients qualified for the trial for having 4 or more positive lymph nodes. Aromatase inhibitors (AIs) were prescribed as the first ET on study treatment in 68.3% of patients and tamox­ifen in 31.4%. At the time of data cutoff, 12.5% of patients had completed 2 years of abemaciclib, while 72.8% remained in the two-year treatment peri­od. The median follow-up time was 15.5 months in both arms.⁴

In total, there were 323 IDFS events observed: 136 (4.8%) IDFS events in the abemaciclib arm and 187 (6.6%) IDFS events in the control arm, with most events being distant recurrences. Abemaci­clib in combination with ET demonstrated a statistically significant improvement in IDFS versus ET alone with two-year survival rates of 92.2% versus 88.7%, respectively (HR 0.75; 95% CI, 0.60 to 0.93; p = 0.01). This equates to an absolute improvement of 3.5% in two-year IDFS rates and a 25% reduction in the risk of an IDFS event relative to ET alone.⁴

The combination of abemaciclib with ET also resulted in an improvement in DRFS compared to ET alone with two-year DRFS rates of 93.6% in the abemaciclib arm and 90.3% in the control arm (HR 0.72; 95% CI, 0.56 to 0.92; p = 0.01). Data for OS was imma­ture, but the study will continue to a final analysis.⁴

Adverse Effects
The safety profile of abemaciclib in the adjuvant setting was consis­tent with the known adverse effects (AE) reported in the meta­static setting. However, due to these AEs, 68.1% of patients in the abemaciclib arm required dose adjustments and 16.6% required discontinuation. The most commonly reported AE in the abemaci­clib arm was diarrhea; arthralgia and hot flash were most common in the control arm (two AEs that were significantly less common in those treated in the combination arm). Grade 3 or higher AEs occurred in 45.9% of patients in the abemaciclib arm and 12.9% of patients in the control arm, with serious AEs occurring in 12.3% and 7.2% of patients, respectively. The most frequently reported serious AE in both arms was pneumonia. Deaths while on study or within 30 days of treatment discontinuation were balanced at 0.5% in each arm.⁴

Summary and Implications
The phase III monarchE trial demonstrated a significant improve­ment in IDFS when abemaciclib is used in addition to standard ET in patients with HR+, HER2-, node-positive, early breast cancer with high risk of recurrence. These patients are at greatest risk for ET resistance within the first 2 years of adjuvant treatment, so a novel therapy to utilize in early-stage disease is warranted and could reduce the risk of resistance, recurrence, and metastases.⁴ Therefore, it is essential to recognize those with an increased risk of recurrence based on disease characteristics and identify when the addition of abemaciclib could be beneficial to these patients.

The monarchE trial represents an exciting new possibility for adjuvant treatment in early breast cancer, for which there have not been new advances in nearly two decades. On the basis of the results from monarchE, the addition of abemaciclib to standard ET should be considered in those with high-risk, node-positive, HR+, HER2-, early breast cancer. However, due to a short median follow-up of 15.5 months, additional follow-up is required to deter­mine continued benefit on later recurrences and overall survival for these patients. The benefit of abemaciclib in patients at low-risk for recurrence is unclear and further studies are warranted. Clinical trials are currently underway assessing the use of other CDK 4/6 inhibitors in high-risk patients with early breast cancer.⁴

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